Reduced effect of gemtuzumab ozogamicin (CMA-676) on P-glycoprotein and/or CD34-positive leukemia cells and its restoration by multidrug resistance modifiers

H. Matsui, A. Takeshita, K. Naito, K. Shinjo, K. Shigeno, M. Maekawa, Y. Yamakawa, M. Tanimoto, M. Kobayashi, K. Ohnishi, R. Ohno

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Abstract

Gemtuzumab ozogamicin (CMA-676), a calicheamicin-conjugated humanized anti-CD33 mouse monoclonal antibody, has recently been introduced clinically as a promising drug for the treatment of patients with acute myeloid leukemia (AML), more than 90% of which express CD33 antigen. However, our recent study suggested that CMA-676 was excreted by a multi-drug-resistance (MDR) mechanism in P-glycoprotein (P-gp)-expressing leukemia cell lines. We analyzed the in vitro effects of CMA-676 on leukemia cells from 27 AML patients in relation to the amount of P-gp, MDR-associated protein 1 (MRP1), CD33 and CD34, using a multi-laser-equipped flow cytometer. The cytocidal effect of CMA-676, estimated by the amount of hypodiploid portion on cell cycle, was inversely related to the amount of P-gp estimated by MRK16 monoclonal antibody (P = 0.004), and to the P-gp function assessed by intracellular rhodamine-123 accumulation in the presence of PSC833 or MS209 as a MDR modifier (P = 0.0004 and P = 0.002, respectively). In addition, these MDR modifiers reversed CMA-676 resistance in P-gp-expressing CD33+ leukemia cells (P = 0.001 with PSC833 and P = 0.0007 with MS209). In CD33+ AML cells from 13 patients, CMA-676 was less effective on CD33+CD34+ than CD33+CD34 cells (P = 0.002). PSC833 partially restored the effect of CMA-676 in CD33+CD34+ cells. These results suggest that the combined use of CMA-676 and a MDR modifier will be more effective on CD33+ AML with P-gp-related MDR.

Original languageEnglish
Pages (from-to)813-819
Number of pages7
JournalLeukemia
Volume16
Issue number5
DOIs
Publication statusPublished - Jan 1 2002

Keywords

  • Antibody-targeted therapy
  • CD33
  • CD34
  • Gemtuzumab ozogamicin (CMA-676)
  • MDR modifier
  • P-glycoprotein

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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    Matsui, H., Takeshita, A., Naito, K., Shinjo, K., Shigeno, K., Maekawa, M., Yamakawa, Y., Tanimoto, M., Kobayashi, M., Ohnishi, K., & Ohno, R. (2002). Reduced effect of gemtuzumab ozogamicin (CMA-676) on P-glycoprotein and/or CD34-positive leukemia cells and its restoration by multidrug resistance modifiers. Leukemia, 16(5), 813-819. https://doi.org/10.1038/sj.leu.2402459